Our long-term goal is to understand better the cellular processes that regulate metastasis and to develop strategy for intervention of metastasis in patients, and this project aims at understanding the pro-metastatic role of FOG2/GATA3 complex in lung adenocarcinoma metastasis. Given that metastasis is the primary cause of death from lung cancer, the No.1 cause of deaths among all malignancies, our studies will potentially have a tremendous public health impact. On the basis of our recent publication, we hypothesize that GATA3 drives lung adenocarcinoma metastasis by forming transcription complexes with its pro-metastatic transcription co- factors. Our preliminary results showed that FOG2 is such a co-factor. Therefore, the primary objective of this application is to elucidate the role of FOG2 in the regulation of GATA3-dependent metastasis. Our central hypothesis is that the transcription complex formed by FOG2 and GATA3 drives metastasis through transcriptional regulation of pro-metastatic genes in lung adenocarcinoma cells. Given that GATA3 acts as metastasis suppressor in breast tumors, our hypothesis opens a new area of investigation into the role of GATA3, by complexing with its pro-metastatic transcription co-factors (e.g. FOG2 identified by our preliminary studies), as a driver of metastasis. To test our hypothesis, we propose to complete two Specific Aims. The first Aim will utilize next-generation sequencing technique to identify putative pro-metastatic transcriptional targets for the FOG2/GATA3 complex; and the role of these genes in invasion and metastasis of lung adenocarcinoma cells will be evaluated by an in vitro invasion assay followed by in vivo metastasis studies using syngeneic metastasis model we have developed. The second Aim will explore several novel mechanisms that regulate FOG2/GATA3 complex: first, we will determine whether the binding of GATA3 to FOG2 is required for EMT, invasion, and metastasis; second, we will determine whether p85 inhibits invasion by binding to FOG2 and sequestering FOG2 in the cytosol, preventing its nuclear translocation; and third, we will determine whether AKT directly phosphorylates and activates FOG2. We expect that the successful completion of this project will advance our current understanding of the mechanisms of lung cancer metastasis and found the basis for developing novel therapeutic strategies.